Synthesis of zearalanone and related compounds and intermediates useful in their synthesis

ABSTRACT

WHEREIN X is an integer having a value from 2 to 6 inclusive and Y is an integer having a value from 2 to 8 inclusive. It also provides for new methods of making compounds useful in the synthesis of zearalanone and related compounds. The new compounds useful as intermediates are 2,7-octadienoic acid; methyl 2,7-octadienoate; sodium ethyl 6-(4-pentenyl)- Beta -dihydroesorcylate; ethyl 6-(4-pentenyl)- Beta dihydroresorcylate; sodium methyl 6-(4-pentenyl)- Beta dihydroresorcylate; methyl 6-(4-pentenyl)- Beta dihydroresorcylate; methyl 3-bromo-6-(4-pentenyl)- Beta dihydroresorcylate; methyl 6-(4-pentenyl)- Beta -resorcylate; ethyl 6-(4-pentenyl)- Beta -resorcylate; ethyl 6-(4-pentenyl)Beta -resorcylate dibenzyl ether; tetrahydropyran-2-yl 4-penten2-yl ether; ethyl 6-(6-oxo-10-tetrahydropyran-2-xyloxyundecyl)Beta -resorcylate dibenzyl ether; and 6-(10-hydroxy-6oxounderyl)- Beta -resorcylic acid dibenzyl ether. Methods for preparing these intermediates are also disclosed. This invention provides a new synthesis for zearalanone and for related compounds having more or fewer carbon atoms in the nonaromatic ring than does zearalanone, which related compounds and zearalanone are represented by the formula

United States Patent 1191 Urry et al.

[451 Aug. 26, 1975 SYNTHESIS OF ZEARALANONE AND RELATED COMPOUNDS ANDINTERMEDIATES USEFUL IN THEIR SYNTHESIS [75] Inventors: Wilbert HerbertUrry, Chicago, Ill;

Guy Towns Mullenbach, Berkeley, Calif.

[73] Assignee: Commercial Solvents Corporation,

Terre Haute, incl.

22 Filed: Mar. 27, 1974 21 Appl.No.:45S,409

Related US. Application Data [62] Division of Ser, No. 247,344, April25, I972, Pat,

No. 3,8l0,9l8.

52 us. Cl..... 260/3432 F; 260/3432 R; 424/279 51 Int. Cl C07d 9/00 53Field of Search 260/3432 F, 343.2 R

[56] References Cited UNITED STATES PATENTS ll/l97l Wendler et al.260/3432 S/l974 Urry et al. 260/3432 OTHER PUBLICATIONS Urry et al.Tetrahedron Letters, No. 27, pp. 3 l09-l4 I966).

Primary Examiner lohn M. Ford Attorney, Agent, or Firm-Morton, Bernard,Brown, Roberts & Sutherland [57] ABSTRACT This invention provides a newsynthesis for zearalanone and for related compounds having more or fewercarbon atoms in the non-aromatic ring than does zearalanone, whichrelated compounds and zearalanone are represented by the formula H CHwherein X is an integer having a value from 2 to 6 inclusive and Y is aninteger having a value from 2 to 8 inclusive. It also provides for newmethods of making compounds useful in the synthesis of zearalanone andrelated compounds.

6-( 4-pentenyl )-)8-resorcylate; ethyl 6-( 4-pentenyl )-B-resorcylatedibenzyl ether; tetrahydropyran-2-yl 4-penten-2-yl ether; ethyl 6-(6-oxolO-tetrahydropyran-2-xyloxyundecyl )-B- resorcylate dibenzyl ether;and 6-( lO-hydroxy--oxounderyl)-B-resorcylic acid dibenzyl ether.Methods for preparing these intermediates are also disclosed.

7 Claims, No Drawings SYNTHESIS OF ZEARALANONE AND RELATED COMPOUNDS ANDINTERMEDIATES USEFUL IN THEIR SYNTHESIS CROSS REFERENCE TO RELATEDAPPLICATIONS This is a division of application Ser. No. 247,344. filedApr. 25, 1972, now US. Pat. No. 3,810,9l8.

BRIEF SUMMARY OF THE INVENTION The present invention is directed to anew process for the manufacture of zearalanone and related compounds,which related compounds and zearalanone are represented by the formulawherein X is an integer having a value from 2 to 6 inclusive and Y is aninteger having a value from 2 to 8 inclusive. More specifically theinvention relates to a process for making all of the foregoing compoundsby a new series of process steps utilizing new intermediate compounds.

it is an object of the present invention to provide a new means forsynthesizing zearalanone and related compounds.

It is another object of the invention to provide new intermediatesuseful in the preparation of zearalanone and related compounds.

It is a further object of the invention to provide new processes forproducing intermediate compounds useful in the synthesis of zearalanoneand related compounds.

DETAILED DESCRIPTION Zearalanone, whose synthesis is one of the objectsof this invention, has the structure illustrated by the formula:

on (a 113 c-o-c- (c11 3 l cs An examination ofthe above formula revealsthat it has one asymmetric carbon atom and the compound produced bysynthesis exists, therefore, as two enantiomorphs designated as D and Lby the older Fischer convention and by R and S by the newer conventionof Cahn and lngold (Cahn, R. S. and lngold C. K., J. Chem. Soc. 6l2.(ll); Cahn, R. 8., J. Chem. Educ. 41, H6 (I964).

Zearalanone produced by the reduction of natural zearalenone has thesame S configuration as does the parent compound. The chemical name forzearalanone is: 6-(l0-hydroxy-6-keto-undecyl)-B-resorcylic acid lactone.Zearalanone was one of the compounds described and claimed in UnitedStates letters Patent No. 3,239,341 issued Mar. 8, I966 to Hodge et al.The compound was prepared by the reduction of a natural productzearalenone, sometimes referred to as F.E.S. resulting from thefermentation of suitable nutrient media using the organism Gibberellazeae (Gordon) on deposit at the Northern Utilization Research andDevelopment Division of the United States Department of Agriculture atPeoria, Illinois under the number NRRL-2830. The reduction was carriedout by hydrogen under the influence of a catalyst such as palladium orplatinum on char in a menstruum of ethyl alcohol (Tetrahedron LettersNo. 27, pages 3,l093,l 14, I966).

The present invention encompasses the discovery that zearalanone can bemade readily by the sequence of reactions illustrated in Chart I.

The first step in the sequence is the pyrolysis of 3-hydroxy-l,S-hexadiene to prepare S-hexenal which is reacted with malonic acid toform 2,7-octadienoic acid. The foregoing acid is esterified by treatmentwith diazomethane and the resulting methyl ester is reacted with thesodium salt of ethyl acetoacetate under the influence of sodiummethoxide in a methanol menstruum to yield the sodium salt of methyl6-(4-pentenyl-B-dihydroresorcylate. The dihydroresorcylate sodium saltis then brominated at low temperature to form methyl 3-bromo-fi-(t-pentenyl)-B-dihydroresorcylate which is de-hydrobrominatedby treatment with sodium cthoxide in an anhydrous ethanol menstruum toprepare ethyl 6-(4-pentenyl)-B-resorcylate. The foregoing resorcylate isreacted with benzyl chloride to yield ethyl 6-(4-pentenyl)-B-resorcylatedibenzyl ether. The foregoing compound is reacted withtetrahydropyran-2-yl 4-penten-2-yl ether by successive treatment with2.3-dimethyl2-butylborane, carbon monoxide, sodium acetate solution, andhydrogen peroxide to give ethyl6-(6-oxo-lO-tetrahydropyran-Z-yloxy-undecyl)-B- resorcylate dibenzylether which is treated with sodium hydroxide and then with hydrochloricacid to yield 6- l0-hydroxy-6-oxo-undecyl )-B-resorcylic acid dibenzylether. The foregoing compound is subjected to the action oftrifluoroacetic anhydride to effect ring closure and form zearalanonedibenzyl ether. On hydrogenation of the dibenzyl ether, (R,S)-zearalanone is formed.

The foregoing sequence of reactions, as well as the reactions describedin the specific examples, can be carried out with appropriate startingmaterials to yield compounds related to (R,S)-zearalanone. They canberepresented by the following formula:

Where X and Y are integers which can take the values:

X 2,3,4,5, or 6 Y 2,3,4,5,6,7, or 8.

The values of X and Y for zearalanone are underscored.

For example, in order to prepare the compound where X=2 and Y=2, itwould be necessary to start with acrolein (CH =CH-CHO) as Compound I inChart I and to react 3-buten-2-ol with dihydropyran to formtetrahydropyran-2-yl 3-buten-2-yl ether as Compound X in the sequence ofreactions in Chart I. l

The compounds produced by the process of this invention are useful inpromoting the growth rate of meat-producing animals. The compounds canbe administered to animals by any suitable method including subcutaneousinjection of pellets under the skin of the ears of mammals as well as byoral and parenteral administrations. For example, the compounds can befor,- mulated into pellets and put under the skin of the ear by asuitable gun or they can be suspended in a medium such as peanut oil andinjected parenterally. The compounds can also be blended with ordinaryfeed containing nutritional values in an amount sufficient to preducethe desired rate of growth and can thus be fed directly to animals.

When the compounds are to be fed directly to animals, the feedcomposition can be prepared containing the usual nutritionally balancedquantities of fats, carbohydrates, proteins, vitamins, and mineralstogether with the chosen compound. Some of these usual dietary elementsare grains, such as ground grain and grain byproducts; animal proteinsubstances such as those found in fish meal and meat scraps; animal andvegetable fats; vegetable proteins like soybean oil meal or peanut oilmeal; vitaminaceous materials, eg. vitamin A and D mixtures; riboflavinsupplements and other vitamin B complex members; antibiotic supplementssuch as zinc bacitracin feed grade; and bone meal and limestone toprovide minerals. A type of conventional feed, material for use withcattle includes alfalfa hay and ground corn cobs together withsupplementary antibiotics and vitaminaceous materials if desired.

The amount of compound administered to the animal,,of course, dependsupon the specific animal, its age and sex, and the desired rate ofgrowth, Usually, administration of from about I to about 100 mg. of acompound per animal per day produces significantly increased growthrate.

The following examples serve to illustrate the invention and set forththe best mode contemplated by the inventors for carrying out theinvention. in the following specific examples, the specific compoundsused are such that in the general formulae presented herein X=3 and Y=5.The specific reactions, however, are illustrative of the more generalreactions when the compounds are'generally represented with X being aninteger of 2 to 6 (i.e., 2,3,4,5 or 6) and Y being an integer of 2 to 8(i.e. 2,3,4,5,6,7 or 8). In the following described general reactionsthe letter "W" and 2" are also used to represent integers with W beingan integer of from O to 6 (i.e., 0,1, 2, 3, 4, 5 or 6) and Z being aninteger from 0 to 4 (i.e. 0, l, 2, 3, or 4). It should also be notedthat a relationship exists between X and Z, such that when zearalanoneor a related compound is described with the X. in the generalformulae.g. X=3, the Z compound should be selected such that Z=X-2 or in thisillustration with X=3, Z would equal 1. Similarly, a relationship existsbetween W and Y, such that when a zearalanone or a related compound isdescribed with the Y in "the general formula e.g. Y=5, the W compoundshould reference substance. The position of the identified peaks may bedescribed by the value:

8 cycles per second from TMS divided by 60 (This relation applies with a60 megaherz instrument) '6 c.p.s. 60 or by 'r 10 minus 8(10-8) The typeof peak is shown by the first letter of the word describing the peak andis followed by a numeral indicating the number of hydrogen atomsinvolved. Examples are as follows:

5,1 singlet. one hydrogen s,2 singlet. two hydrogens d,1 doublet, onehydrogen 1,2 triplet, two hydrogens m,4 multiplet. four hydrogens broads,] a broad singlet for one hydrogen which may result from OH, COOH,CHO.

EXAMPLE 1 This example illustrates the preparation of S-hexenal l by thefollowing reaction:

3-hydroxy-1 ,S-hexadiene 190 g, 1.94 mol, of 3-hydroxy-1,5-hexadiene wasslowly distilled through a 50 cm column packed with 3 mm Pyrex helicesmaintained at 380. Fractional distillation of the pyrolysis mixture gave1 1 1.2 g, 1.14 mol (59 per cent), of S-hexanal; bp 575 (57 mm); bp120-2l (760 MM).

Although S-hexenal is not a new compound, it is not readily availableand, therefore, the above described step describes a known method forthe preparation coon CH 1 ll ;2= (c1-| CHO lien Heat ca coon (cx h 1 in[I in o A reaction mixture containing 76.9 g, 0.784 mol, of S-hexenal 1,90.0 g, 0.865 mol, of malonic acid, and 145 m1 of pyridine was stirredat 25 under nitrogen for 60 hr. An additional 45.0 g of malonic acid wasadded to it, and stirring was continued for 24 hr at 25. It was thenheated on a steam bath until carbon dioxide evolution ceased (20 hr).Water (145 ml) was added to it, and the resulting mixture was extractedwith ether (3 X 200 ml). The extract was washed with dilute hydrochloricacid (2n, 2 X ml), water (2 X 50 ml), and dried (Na SO Fractionaldistillation gave 83.0 g, 0.593 mol (76 per cent), of ll: bp 8687(0.15mm); nmr (CDCl TMS) 812.34 (5, 1, COOH), 7.26 and 6.98 (2 t, l, .1 =15.7Hz, J 7 Hz, CH CH=CH), 5.97 and 5.70 (2 t, l, J 15.7 Hz, J 1 Hz, CHCOO),5.72, 4.92 and 4.88 (3 m, 3, CH=CH 2.12 (br m, 4, CH CH=CH and 1.60 ppm(br m, 2, CH CH CH Anal. Calcd. for C H O c, 68.6; H, 8.6. Found: C,68.6; H, 8.7.

EXAMPLE 3 This example illustrates the preparation of methyl2,7-octadienoate, 111, by the following general reaction wherein W=3:

A solution of diazomethane in ether was added to a cold (0) solution of83.0 g, 0.592 mol, of 11 in 200 ml of ether until a yellow colorpersisted. Evaporation of the reaction mixture gave 90.3 g of crude 111that was fractionally distilled to give 802 g, 0.520 mol (88 per cent)of 111: bp 44-45 (0.70 mm); nmr (CDCl TMS) 87.04 and 6.78 (2 t, 1, J15.7 Hz, J 7 Hz, CH CH=CH), 5.87 and 5.61 (2 t, l, J 15.7 Hz, J Hz,CHCO), 5.72, 4.92 and 4.88 (3 m, 3, CH=CH 3.67 (s, 3, CH 2.12 (br m, 4,CH CH=CH), and 1.58 ppm (br m, 2, CH CH CH Ana]. Calcd. for C H O C,70.2; H, 9.1. Found: C,

thereof. 70.1; H, 9.2

EXAMPLE 2 EXAMPLE 4 This example illustrates the preparation of 2,7-This example illustrates the preparation ofethyl 6-(4- octadienoic acid11 by the following general reaction pentenyl)-B-dihydroresorcylatesodium salt IV by the wherein W=3: following reaction wherein W 3:

0 on 1 ll 2 0 o crocu cHs IH .c-o-cn cu fin (c11 C2H5ONa I 2 3 /c\ onNae 3 g Nao (C11 CH=CH oocii III IV o I 1 C-OCH CH Iv set 2 X B0 -tcumcihcn 1.4 g, 0.626 mol, of freshly-distilled ethyl acetoactate wasadded dropwise to a stirred solution of soium ethoxide prepared from14.4 g, 0.626 g-atom of )dium and 200 ml of ethanol under nitrogen. Thereilting solution was held at reflux while 80.2 g, 0.521 10l, of 111 wasadded dropwise, and then such heating as continued with mechanicalstirring for 22 hr. The )lid that precipitated during the reaction andwhile the iixture was cooled to 0 was removed on a filter, and waswashed with ether to give 11080 g, 0.404 mol ?8 per cent), of white 1V:nmr (D 0, DSS, integration Fsome ring hydrogen atoms not given sincethey ex- 1anged)55.72, 4.92 and 4.88 (3 m, 3, CH =CH), 4.22 1, 2, J 7Hz, COOCH 3.18 (d, J 10 Hz, CCOO), 2.20 (m,OCCH CH), 2.00 (br m, 2, HCH=CH 1.33 (br m, 5, (CH(CH CH and 26 ppm (t, 3, J 7 Hz, CH Then asolution of 3.00 g, 0.0109 mol, of IV in 50 ml 7water was acidified with3N hydrochloric acid and 1e resulting mixture was extracted with ether(4 X 25 l). The extract was washed with water (4 X 25 ml), 716d (MgSO,),and evaporated in a Rinco evaporator, well known and widely used vacuumrotary evapora- Ir hereinafter referred to as Rinco", to give a residuehich crystallized from ligroin (bp 60-68) to give 37 g, 0.00942 mol (86per cent) of ethyl 6 (4- :ntenyl)-B-dihydroresorcylate: mp 72.5-73.5;nmr jDCl TMS) 812.32 (s, 0.2, 2-OH), 9.75 (s, 0.8, OH), 5.72, 4.92 and4.88 (3 m, 3, CH=CH 5.52 (s, 8, 3-CH), 4.29 and 4.22 (2 q, 2, J 7 Hz,COOCH 0, l2 (s, 0.4, 3-CH;), 3.15 (d, 0.8, J 10 Hz, l-CH), 45 (m, ca. 2,-CH 2.06 (br m, 2, CH CH=CH 36 (br m, 5, CH(CH CH and 1.29 ppm (t, 3, JHz, CH Anal. Calcd. for C H O C, 66.7; H, 8.0. )und: C, 66.7; H, 8.0.

-pentenyl)-B-dihydroresorcylate sodium salt V by e following generalreaction wherein W 3:

l '0 C )w CH 0:1;

NIO

O /L -O-CH The reaction mixture was prepared by dropwise addition of70.7 g, 0.598 mol, of ethyl acetoacetate to a solution of 32.3 g, 0.598mol of sodium methoxide in 130 ml of methanol stirred under nitrogen,and then 742 g, 0.482 mol of 111 was also added dropwise. It was held atreflux with mechanical stirring for 20 hr. About ml ofits solvent wasremoved under vacuum, and it was cooled to 0. A precipitate that formedduring the above was removed on a filter and washed with ether until itwas white to give 84.7 g, 0.326 mol (68 per cent), of V: nmr (D 0, DSS):again exchange of hydrogen atoms on the ring occurred) 85.72, 4.92 and4.88 (3 m, 3, CH=CH 5.07 (s, OCCHCO), 3.18 (d, J Hz, HCCOO), 2.20 (m,OCCH CH), 2.00 (br m, 2, CH CH=CH and 1.33 ppm (br m, 5, CH(CH CH Thenmr spectrum is nearly the same as [V above, except for the alkoxyabsorptions.

The compound V may readily be acidified to prepare methyl6-(4-pentenyl)fi-dihydroresorcylate Va by the following general reactionwherein W 3:

-O-CH Methyl 6-(4-pentenyl)-B-dihydroresorcylate when W 3 And in turnthe compound Va may be reacted with sodium hydroxide to form V.Converting the sodium salt V to Va and then treating Va with sodiumhydroxide to again form the sodium salt V, of course, provides anefficient method for preparing relatively pure V.

EXAMPLE 6 This example illustrates the preparation of methyl 3-bromo-6-(4-pentenyl)-B-dihydroresorcylate V1 by the following generalreaction wherein W 3:

I Br c- BI: tea cm-czii H (CH CH-CH A solution of 58.2 g, 0.326 mol, ofbromine and 193.1 g, 1.87 mol, of sodium bromide in 200 ml of water wasLac,

added dropwise over 6 hr to a rapidly stirred solution of 84.7 g, 0.326mol, ofV in 700 ml of water cooled to After 30 min, the solid that hadprecipitated was removed by filtration. lt was dissolved in 200 ml ofether, and the resulting solution was washed with water (3 X 150 ml),and briefly dried (MgSOJ. It was evaporated (Rinco, 25), and the residuewas recrystallized from 200 ml of ether and pentane to give 70.4 g,0.222 mol (68 per cent), of white crystalline VI: mp 9l-93: nmr (CDClTMS) 88.10 (s, 1, 4-0H), 5.72, 4.92 and 4.88 (3 m, 3, CH=CH 3.77 (s, 3,CH 3.35 (d, l, J Hz, HCCOO), 2.72 (dd, 1, J =20.4 HZ. 14x 11.0 Hz, OCCHCH), 2.43 (dd, 1, J 20.4 Hz, J 8.6 Hz, OCCH CH), 2.06 (br m, 2,CH,CH=CH=). and 1.45 ppm (br m, 5, CH(CH,),CH,). Anal. Calcd. forc,,,H,,0,Br; C, 49.2; H, 5.4; Br, 25.2. Found: C, 48.9; H, 5.7; Br,25.2.

In Example 6, the temperature at which the reaction of bromine withCompound V is allowed to occur is kept at 0C in order to minimize thereaction of bromine with the double bond in the side chain of thecompound. Temperatures up to 25C could be used for this reaction but 0Cis preferred. A lower temperature limit of about l0C is set since therate of the desired reaction becomes too low at temperatures much below-l0C because the reaction mixture would freeze.

EXAMPLE 7 This example illustrates the preparation of methyl6-(4-pentenyl)-B-resorcylate Vll by the following general reactionwherein W 3, and R methyl:

R methyl or ethyl A solution of 21.5 g, 0.0678 mol, of V1 and sodiummethoxide (prepared from 15.6 g, 0.678 g-atom of sodium) in 350 ml ofanhydrous methanol was maintained at reflux under nitrogen for 9 hr.Then 200 ml of methanol was evaporated under vacuum. The reactionmixture was held at 0 while enough water to give 400 ml of the mixturewas added to it. It was acidified with sulfuric acid (6N), and extractedwith ether (3 X 200 ml). The extract was washed with water (4 X 200 ml),and it was decolorized with charcoal, and evaporated Rinco) to yield14.9 g, 0.0632 mol (93 per cent), of crude Vll. Purification by drycolumn chromatography (300 g, Silica Gel H, 10 per cent ethyl ether inVIIA EXAMPLE 8 This example illustrates the preparation of ethyl6-(4-pentenyl)-B-resorcylate Vlll by the following general reactionwherein W 3 and R ethyl:

O O O B: I! liOCH O 3 C-OR I10 (CH Cli=Cli (C11 CH=C1I VI VIII Asolution containing 19.33 g, 0.0610 mol, of V1, and sodium ethoxide(prepared from 9.00 g, 0.391 g-atom, of sodium and in the 250 ml ofethanol) was held at reflux under nitrogen for 6 hr, and then it wasevaporated under vacuum until its volume was about 100 ml. It wasdiluted with water to 300 ml, and acidified with sulfuric acid (6N)while it was held at 0. The resulting mixture was extracted with ether(3 X 150 ml). The extract was then washed with water (4 X100 ml),decolorized with charcoal, and evaporated (Rinco) to yield 14.0 g,0.0562 mol (92 per cent), of crude Vlll. Dry column chromatography (300g Silica Gel H, 10 per cent ethyl ether in methylene chloride) gave 9.15g, 0.0366 mol per cent), of Vlll: nmr (CDCL TMS) 511.95 (s, l, 4-OH),7.42 (s, 1, 4OH), 6.33 and 6.30 (2 d, 2, .l 2 Hz, aromatic CH), 5.72,4.92 and 4.88 (3 m, 3, CH=CH,), 4.40 (q, 2, .l 7 Hz, COOCH 2.85 (t, 2,.l 7 Hz, ArCH 2.03 (m, 2, CH CH=CH 1.64 (br m, 2, CH,CH CH and 1.40 ppm(t, 3, J 7 Hz, CH Except for the expected differences, this nmr spectrumis the same as that of Vll.

In Example 8 the de-hydrobromination of compound VI can be effected attemperatures in the range 60Cl20C but a temperature near C is preferred.At a temperature of 80C the rate of dehydrobromination is reasonablyfast and side reactions are minimal.

The de-hydrobromination step could be carried out in a menstruum of analcohol other than ethanol, for example methanol or butanol.

EXAMPLE 9 This example illustrates the preparation of ethyl6-(4-pentenylHi-resorcylate dibenzyl ether 1X by the following generalreaction wherein W 3 and R ethyl:

= methyl or ethyl A mixture of 31.5 g, 0.126 mol, V111, 60.5 g of whyous potassium carbonate, and 31.5 ml 0.274 mol, of :nzyl chloride in 300ml of dimethylsulfoxide was irred on a steam bath for 6 hr. 1.0 1. ofwater was lded to it while it was stirred, and then it was held lernightat 15. The product that had crystallized as collected on a filter, andit was recrystallized from mixture of ethyl ether and ligroin (bp 60-68)to give 5.5 g, 0.106 mo] (84 per cent), of IX: mp 49-51; nr (CDCl TMS)87.32 (m, 10, C H 6.44 (s, 2, aroatic CH), 5.72, 4.92 and 4.88 (3 m, 3,CH=CH 98 and 4.96 (2 s, 4, C H CH 4.28 (q, 2, .1 7 Hz, OOCH,), 2.58 (t,2, .1 7 Hz, ArCH 2.00 (m, 2, H CH=CH 1.64 (br m, 2, CH CH CH and 1.23 :m(t, 3, J 7 Hz, CH Anal. Calcd. for C H O,: 78.2; H, 7.0. Found: C, 78.0;H, 6.9.

EXAMPLE 10 This example illustrates the preparation of tetrahy-'opyran-2-y1 4-penten-2-yl ether X by the following :neral reactionwherein Z l:

trogen for 20 hr. Then several sodium hydroxide pellets were added toit, and it was stirred for another 0.5 hr. Its fractional distillationgave 42.7 g, 0.251 mo] (86 per cent), of the ether X: bp 48.549.5 (2.4mm); nmr (CDCl TMS) 55.72, 4.92 and 4.88 (3 m, 3, CH=CH 4.63 (m, 1,OCHO), 3.64 (br m, 3, CH O and CH -,CHO), 2.23 (br m, 2, CH CH=CH 1.58(br m, 6, CH(CH );,CH and 1.13 ppm (d, 3, J 7 Hz, CH Anal. Calcd. for C,,H, O,: C, 70.6; H, 10.7. Found; C, 70.8; H, 10.6.

In Example 10, the formation of Compound X is carried out at atemperature of 25C. The temperature should not be allowed to go muchabove this value, but a temperature as low as 20C can be used. The rateof ether formation is, of-course, lower the lower the temperature atwhich the reaction is effected.

EXAMPLE 11 cH -c1l c BN2 1120 co Ix I1 0 Cl1 COONa R methyl or ethyl2.19 ml, 0.00465 mol. of 2.12 M diborane in tetrahydrofuran was injectedvia rubbr septum into a one neck, ml round bottomed flask containing 15ml of tetrahydrofuran (distilled from calcium hydride) and equipped witha nitrogen seal. efficient magnetic stirring and ice bath cooling. Then0.550 ml, 0.391 g, 0.00465 mol, of 2,3-dimethyl-2-butene was injected.After 1.25 hr. of stirring at 0, 0.792 g, 0.00465 mol, oftetrahydropyran-Z-yl 4-penten-2-y1 ether X was injected over 2 min whilecooling and stirring was continued. After 1.25 hr, 200 g, 0.00465 mol,of 1X In 7 ml of tetrahydrofuran was injected into the rapidly stirredand cooled solution during two min. An additional 5 m1 oftetrahydrofuran, used to rinse the syringe, was also injected. andstirring at 0 was maintained for 14.5 hr.

Then 0.167 ml, 0.00928 mol, of water was injected, a large-borehypodermic needle was placed through the septum, and the flask, soequipped, was sealed in a high pressure autoclave that had beenthoroughly flushed with nitrogen. The autoclave was then heated at 60for l 1 hr under 54 atm of carbon monoxide (C.P.). During the first 2hours the autoclave was inverted four times. At the end of the heatingperiod, it was slowly vented, and the flask was again placed under anitrogen seal. At 25and with rapid stirring, 1.55 ml, 0.00465 mol, of3.0 M sodium acetate and 1.55 ml, 0.0137 mol, of 30 per cent hydrogenperoxide were injected in rapid succession. The reaction mixture wasmaintained at 50 in an oil bath with stirring for 3 hr. It was thenevaporated (Rinco), and the residue was extracted with ether. Theextract was washed with saturated potassium carbonate (1 X 15 ml) andwater (3 X 15 ml). It was dried (Na S and K CO and evaporated to give2.61 g of viscous residue. Nmr analysis indicated that 55-65 per cent ofthis crude product was X1 ca 1.56 g, 0.00248 mol (53 per cent); nmr(CDCl- TMS) 87.32 (m, 10, C H 6.44 (s, 2, aromatic CH), 4.98 and 4.96 (2s, 4, C H CH 4.66 (br m, 1 OCHO), 4.28 (q, 2, J 7 Hz, COOCH 3.65 (br m,3, CH,O and HCO), 2.58 (t, 2, J 7 Hz, ArCH 2.37 (t, 4, J 7 Hz, CH COCH1.55 (br m, 16, COCH (CH Cl-1 COCH,(CH CH, and CH(CH -,CH,O), 1.23 (t,3, J 7 Hz, CH CH and 1.14 ppm (d, 3, J 71-12, CHCH 1n Example 1 1, thereaction involving carbon monoxide is conducted at 60C. Temperaturesmuch above this value give unwanted side reactions. Lower temperaturesdown to room temperature can be used if a longer reaction time can betolerated. An increase in carbon monoxide pressure will, of course,increase the reaction rate and make lower temperatures more acceptable.

EXAMPLE 12 This example illustrates the preparation of 6-(10hydroxy-6-oxo-undecyl)-B-resorcylic acid dibenzyl ether X11 by thefollowing general reaction wherein R =ethyl, X 3 and Y 5:

CBHSCHZO o o OR q 0 x1 l (C11 'C-(C11 -CH-Cl1 l (:11 O R methyl or ethylc ll 1) NaOll c n cu o 0 ll c-on 11 o (cu -c-(cn -cn l 1 (p1 on c 11 XIIA solution of 1.40 g ofcrude X1 (ca. 60 per cent purity; 0.00133 mol ofX1) in 30 ml of dimethylsulfoxide and 18 ml of 20 per cent sodiumhydroxide was gently refluxed under nitrogen for 7.5 hr It was thenacidified with dilute hydrochloric acid. The organic layer was dilutedwith chloroform, separated, and washed with water 3 X 20 ml).Evaporation of this chloroform solution (Rinco) gave a residue. It wasdissolved in 1.0 ml of concentrated hydrochloric acid and 50 ml ofacetone, and the reaction mixture was held at reflux under nitrogen for15 min. Then 200 ml of water was added to it, and the resulting mixturewas evaporated (Rinco) to remove low boiling impurities. A solution ofthe residue in 50 ml of ether was washed with water until neutral, dried(MgSO and evaporated (Rinco) to leave 1.1 1 g of residue containing ca.45 per cent (from nmr spectrum), ca. 0.498 g, 0.00096 mol (72 per centyield) of X11: nmr (CDCl TMS) 68.88 (br s, 2, COOH and OH), 7.33 (s, 10,C 11 6.45 (s, 2, aromatic CH), 5.01 and 4.98 (2 s, 4, C H CH 3.77 (br m,1, CHCHQ, 2.75 (t, 2, J 6 Hz, ArCH 2.33 (t, 4, J 7 Hz, CH -COCH 1.53 (brm, 10, CH (CH CH and (CH Cl-1), and 1.14 ppm (d, 3, J 6.5 Hz. CH;,).

The temperature at which Compound X1 is treated with sodium hydroxidecan be increased from 120C up to about C. Temperatures considerablybelow 120C can be used, for example 80C, but the time for the reactionto go to completion is greatly increased.

EXAMPLE 13 This example illustrates the preparation of zearalanonedibenzyl ether X111 by the following general reaction wherein X 3 and Y5:

XIII

A solution of 0.591 g of crude X11 (ca. 45 per cent purity preparedabove) and 0.239 g, 1.14 X 10 mol, of freshly prepared trifluoroaceticanhydride in 200 ml of anhydrous benzene containing 5 g of Linde 3Amolecular sieves was stirred for 23 hr at 6 under nitrogen. Thenanalysis ofit by thin layer chromatography (Silica iel, 10 per centethyl acetate in benzene) gave no indiation of XI". Consequently, asecond equivalent, .239 g of trifluoroacetic anhydride was added, andtirring at 6 was continued. For the same reason, addional equivalents ofanhydride were added according the following schedule: 78 hr, thirdequivalent; 127 r, fourth equivalent; 142 hr, fifth and sixthequivalent. .fter 218 hr thin layer chromatography as above still ave noclear evidence for the presence of X1, but 50 ll of per cent sodiumhydroxide was added to the rection mixture while it was stirred. Theorganic layer 'as separated and washed with hydrochloric acid 4N),saturated sodium chloride solution (4 X 50 ml), nd water 1 X 50 ml).After it had been dried MgSO it was evaporated to give 0.54 g of residue'hich was purified by dry column chromatography (40 of Silica Gel H, percent ethyl acetate in benzene). esidual product from fractionscontaining Xlll (tlc) as recrystallized from ligroin (60-68) to give0.0566 1.13 X 10 mol (ca. 22 per cent based upon Xll in s crude mixture)of Xlll: mp 103-105; mass specum (70 eV) m/e (rel intensity) 500(6),482(2), 09(2), 391(2), 181(6), 91(100), 69(2), 65(4), 32(2), 8(8). Themass spectrum is identical to that of the dienzyl ether of zearalanoneprepared from natural zeailenone. The melting point is the same as thatof XI" repared via other methods, and mixed melting points ere notdepressed.

EXAMPLE 14 This example illustrates the preparation of DL- earalanoneXIV by the following general reaction herein X 3 and Y 5:

I H CH O D H H l l lll Pd or. charcoal XIV DL-Zearalanonc when X 3(R,S)Zcaralanone andY=S action mixture was then filtered and evaporated6 .inco), and the residue was purified by preparative in layerchromatography (Silica Gel, 10 per cent 1yl acetate in benzene) to give0.054 g. 0.0001 69 mol 4 per cent), of XIV; mp 208-2l0 (from acetone);1r (acetone-d TMS) 81 1.87 (br s, l, 2OH), 6.32 (d,

1, J =25 Hz, aromatic CH), 6.28 (d, l, .l 2.5 Hz, aromatic CH), 7.34 (brs, l, 4-OH), 5.20 (br m, l, COOCH), 3.02 and 2.74 (2 br m, 6, ArCH andCH COCH 2.50 to 1.20 (very br m, 10, CH (CH CH and CH(CH CH and 1.32 ppm(d, 3, J 6.0 Hz, C 3); mass spectrum eV) m/e (rel intensity) 320(35),302(19), 251(19), 177(36), 163(98), (35), 69(46), 55(76), 41(100). Thesenmr and mass spectra are identical to those of naturallyderivedS-zearalanone.

We claim:

1. A compound of the formula wherein X is an integer having a value offrom 2 to 6.

2. A method for the chemical synthesis of (R,S)- zearalanone whichcomprises the steps of a. reacting tetrahydropyran-Z-yl 4'penten-2-ylether with alkyl 6-(4-pentenyl)-B-resorcylate dibenzyl ether and carbonmonoxide to prepare alkyl 6-(6-0x0-1O-tetrahydropyran-2-yloxy-undecyl)-B- resorcylate dibenzyl ether,wherein said alkyl is methyl or ethyl;

b. reacting alkyl 6-(6-oxo-lO-tetrahydropyran-Z-yloxy-undecyl-B-resorcylate dibenzyl ether with base and with acid toprepare 6-(l0-hydroxy-6- oxo-undecyl)-B-resorcylic acid dibenzyl ether;

c. treating 6-( l0-hydroxy-6-oxo-undecyl)-B- resorcylic acid dibenzylether with trifluoroacetic anhydride in dilute solution to prepare(R,S)- zearalanone dibenzyl ether;

(1. reacting (R,S)-zearalanone dibenzyl ether with hydrogen to prepare(R.S)-zearalanone.

3. The method of claim 2 wherein the alkyl 6-(4pentenyl )-[3-res0reylatedibenzyl ether is prepared y a. reacting 5-hexenal with malonic acid toprepare 2,7-octadienoic acid;

b. reacting 2,7-octadienoic acid with diazomethane to prepare methyl2,7-octadienoate;

c. reacting methyl 2,7-octadienoate with the sodium salt of acetoaceticester in the presence of methanol and sodium methoxide to prepare thesodium salt of methyl 6-(4-pentenyl)-B-dihydroresorcylate;

d. reacting the sodium salt of methyl 6-(4-pentenyl)-B-dihydroresorcylate with bromine to prepare methyl3-bromo-6-(4-pentenyl)-B-dihydroresorcylate;

e. reacting methyl 3-br0mo-6-(4-pentenyl-B-dihydroresorcylate with asodium alkoxide selected from the group consisting of sodium methoxideand sodium ethoxide to prepare alkyl 6-(4-pentyl)-B- resorcylate,wherein the alkyl is methyl or ethyl; and

f. reacting alkyl 6-(4-pentenyl)-B-resorcylate with benzyl chloride toprepare alkyl 6-(4-pentenyl)B- resorcylate dibenzyl ether.

4. The method of claim 2 wherein the alkyl is methyl.

5. The method of claim 2 wherein the alkyl is ethyl.

6. The method of claim 3 wherein the sodium alkoxide is sodium methoxideand the alkyl is methyl.

7. The method of claim 3 wherein the sodium alkox ide is sodium ethoxideand the alkyl is ethyl.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO.3,901,922

DATED August 26, 1975 INVENTORtS) WILBERT HERBERT URRY and GUY TOWNSMULLENBACH It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below;

Column 3, line 36, should appear X 2, i, 4, 5, or 6 and line 37, shouldappear Y 2, 3, 4, 5 6, 7, or 8 Column 6, line 22, "Zn" should appear 2NColumn 9, line 53, a left hand parenthesis should appear before "Rinco".

Column 11, line 67, "4-penten2-ol" should appear 4-penten-2-ol Column12, line 55, "rubbr" should appear rubber Signed and Scaled this thirdDay Of February 1976 [SEAL] Attest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner uf'Parenlsand Trademarks

1. A COMPOUND OF THE FORMULA
 2. A method for the chemical synthesis of(R,S)-zearalanone which comprises the steps of a. reactingtetrahydropyran-2-yl 4-penten-2-yl ether with alkyl 6-(4-pentenyl)- Beta-resorcylate dibenzyl ether and carbon monoxide to prepare alkyl6-(6-oxo-10-tetrahydropyran-2-yloxy-undecyl)- Beta -resorcylate dibenzylether, wherein said alkyl is methyl or ethyl; b. reacting alkyl6-(6-oxo-10-tetrahydropyran-2-yloxy-undecyl-Beta -resorcylate dibenzylether with base and with acid to prepare 6-(10-hydroxy-6-oxo-undecyl)-Beta -resorcylic acid dibenzyl ether; c. treating6-(10-hydroxy-6-oxo-undecyl)- Beta -resorcylic acid dibenzyl ether withtrifluoroacetic anhydride in dilute solution to prepare(R,S)-zearalanone dibenzyl ether; d. reacting (R,S)-zearalanone dibenzylether with hydrogen to prepare (R,S)-zearalanone.
 3. The method of claim2 wherein the alkyl 6-(4-pentenyl)- Beta -resorcylate dibenzyl ether isprepared by a. reacting 5-hexenal with malonic acid to prepare2,7-octadienoic acid; b. reacting 2,7-octadienoic acid with diazomethaneto prepare methyl 2,7-octadienoate; c. reacting methyl 2,7-octadienoatewith the sodium salt of acetoacetic ester in the presence of methanoland sodium methoxide to prepare the sodium salt of methyl6-(4-pentenyl)-Beta -dihydroresorcylate; d. reacting the sodium salt ofmethyl 6-(4-pentenyl)- Beta -dihydroresorcylate with bromine to preparemethyl 3-bromo-6-(4-pentenyl)- Beta -dihydroresorcylate; e. reactingmethyl 3-bromo-6-(4-pentenyl- Beta -dihydroresorcylate with a sodiumalkoxide selected from the group consisting of sodium methoxide andsodium ethoxide to prepare alkyl 6-(4-pentyl)- Beta -resorcylate,wherein the alkyl is methyl or ethyl; and f. reacting alkyl6-(4-pentenyl)- Beta -resorcylate with benzyl chloride to prepare alkyl6-(4-pentenyl)- Beta -resorcylate dibenzyl ether.
 4. The method of claim2 wherein the alkyl is methyl.
 5. The method of claim 2 wherein thealkyl is ethyl.
 6. The method of claim 3 wherein the sodium alkoxide issodium methoxide and the alkyl is methyl.
 7. The method of claim 3wherein the sodium alkoxide is sodium ethoxide and the alkyl is ethyl.